Design, synthesis and biological evaluation of some novel phosphoramidate prodrugs

• Main Author: Daverio, Felice
• Published: Cardiff University 2006
• Subjects: 615.1
• Online Access: http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.583862

An introduction to the work presented within this thesis involves a brief overview of nucleosides, nucleotides and nucleic acids. Descriptions of the prodrug concept and pronucleotide approaches are also given. The work presented within this thesis describes the synthesis and biological evaluation of a number of phosphoramidate derivatives of some nucleoside analogues. This includes phosphoramidates of E-5-2-bromovinyl-2'-deoxyuridine BVdU, 2//3'-dideoxyadenosine ddA, 9-p-D-arabinofuranosyl-2-fluoroadenine F-Ara-A, fludarabine, and 2',2'-difluorodeoxycytidine Gemzar, gemcitabine. Extensive SAR studies of the anticancer lead thymectacin phenyl-methoxy-L-alaninyl-BVdU phosphoramidate revealed a significant enhancement of potency in vitro in colon and prostate cancer cell lines. A small series of phosphoramidates of the anticancer agents gemcitabine and fludarabine was synthesised and evaluated for their cytotoxic activities but not significant improvement in in vitro activity was observed. Finally, a series of phosphoramidate derivatives of 2',3'-dideoxyadenosine was synthesised and tested as inhibitors of endothelium-derived hyperpolarizing factor EDHF. This represents the first example of the application of phosphoramidate derivatives as non antiviral/anticancer agents.